Basically substituted 2,4-(1h,3h)-quinazolindione derivatives

ABSTRACT

WITH PHOSGENE OR WITH A LOWER ALKYL CHLOROFORMATE. PHARMACOLOGICALLY VALUABLE, BASICALLY SUBSTITUTED 2,4(1H,3H)-QIUNAZOLIDIONE DERIVATIVES HAVING THE FORMULA   2,4-DI(O=),3-(R&#39;&#39;-CH2-CH(-OOC-C6H4-(R2)M)-CH2-),(R1)N-1,2,   3,4-TETRAHYDROQUINAZOLINE   WHEREIN R&#39;&#39; IS SELECTED FROM A RADICAL SELECTED FROM THE GROUP CONSISTING DI-C1-C4-ALKYLAMINO, N-MERHYLBENZYLAMINO, N-METHYL-C-CYCLOHEXYLAMINO, N-METHYLALLYLAMINO, N-METHYL-PIPERAZINO, N-METHYL-N-(PIPEREDINO-N-PROPYL)AMINO, N-METHYL-N-(METHOXY-N-PROPYL)AMINO, HEXAMETHYLENEIMINO, MORPHOLINO, THIOMORPHOLINE, PYRROLIDINO AND PIPERIDINO, R1 IS METHOXY, R2 STANDS FOR ALKOXY GROUPS HAVING 1-4 CARBON ATOMS, M STANDS FOR AN INTEGER SELECTED FROM THE GROUPS 1, 2 AND 3, AND N STANDS FOR AN INTEGER SELECTED FROM THE GROUPS 2 AND 3 HAVING THE FORMULA   2,4-DI(O=),3-(R-CH2-CH(-OH)-CH2-),(R1)N-1,2,3,4-TETRA-   HYDROQUINAZOLINE   WHEREIN R1 HAS THE ABOVE-GIVEN MEANING, R IS IDENTICAL WITH R&#39;&#39; OR, IN CASE R&#39;&#39; CONTAINS AN ACYLOXY RADICAL OF THE FORMULA   (R2)M-C6H4-COO-   SAID R MAY ALSO REPRESENT THE RADICAL OF THE UNDERLYING HYDROXY COMPOUND WITH AN ALKOXY BENZONIC ACID OF THE FORMULA   (R2)M-C6H4-COOH   OR A FUNCTIONAL DERIVATIVE THEREOF, OR BY CYCLIZING SUBSITUTED O-AMINOBENZAMIDES HAVING THE FORMULA   (2-NH2,(R1)N-PHENYL)-CO-NH-CH2-CH(-OOC-C6H4-(R2)M)-CH2-R&#39;&#39;

US. Cl. 260-2472 A 6 Claims ABSTRACT OF THE DISCLOSURE Pharmacologically valuable, basically substituted 2,4- (1H,3H)-qiunazolidione derivatives having the formula N-CHz-OH-CHz-R N to H wherein R is selected from a radical selected from the group consisting of diC C alkylamino, N-methylbenzylamino, N-methyl-N-cyclohexylamino, N-methylallylamino, N-methyl-piperazino, N-methyl-N-(piperidino-n-propyl) amino, N methyl-N- (methoxy-n-propyl) amino, hexamethyleneimino, morpholino, thiomorpholino, pyrrolidino and piperidino; R is methoxy; R stands for alkoxy groups having 1-4 carbon atoms; m stands for an integer selected from the groups 1, 2 and 3; and It stands for an integer selected from the groups 2 and =3 having the formula Hz- CH- C Hz-R u (1) O H wherein R has the above-given meaning, R is identical with R or, in case R contains an acyloxy radical of the formula said R may also represent the radical of the underlying hydroxy compound with an alkoxy benzoic acid of the formula or a functional derivative thereof; or by cyclizing substituted o-aminobenzamides having the formula "United States Paten 0 3,740,398 Patented June 19, 1973 ice with phosgene or with a lower alkyl chloroformate.

The present invention relates to new, pharmacologically valuable, basically substituted 2,4-(1-I-I,3H)-quinoazolindione derivatives having the formula R means the radical of a secondary aliphatic, cycloaliphatic, araliphatic amine having 2 to 10 carbon atoms or of a 5, 6 or 7-membered heterocyclic nitrogen base, which contains in the nucleus besides the nitrogen atom a corresponding number of methylene groups as Well as iurther nitrogen atoms, and 0 or an S atom, said radical being bound via a nitrogen atom,

R stands for lower alkoxy groups having 1 to 4 carbon atoms which are preferably in the 6,7 or 6,7,8-position,

R represents alkoxy having 1 to 4 carbon atoms,

m stands for the integers 1, 2 or 3 and it means the integers 2 or 3.

Furthermore, the present invention relates to processes for the production of said compounds.

The radical of a secondary amine R which is bound via a nitrogen atom may derive in the aliphatic series from mono and diamines, such as dialkylamines, alkylalkenylamines, alkylenediamines, hydroxyalkylamines and alkoxyalkylamines.

Such amines are for instance: dimethylamine, diethylamine, allylmethylamine, N,N-diethyl-N'-methylethylenediamine, N,N-diethyl-N-methylpropylenediamine, N- methylethanolamine, N-methylpropanolamine, N-isopropylethanolamine, N-butylethanolamine, N-benzylethanolamine, N-methylmethoxypropylamine, N-methylethoxypropylamine.

Cycloaliphatic amines may be for instance: N-methylcyclopropylamine, N-methylcyclohexylamine.

Amines of the araliphatic series may be for instance: phenalkylalkylamines such as benzylmethylamine, phenethylmethylamine.

Heterocyclic nitrogen bases may be for instance: 5,6 and 7-membered heterocyclic nitrogen bases such as pyrrolidine, morpholine, thiornorpholine, piperidine, N- methylpiperazine, N-phenylpiperazine, N-(B-hydroxyethyl)-piperazine, N-(w-hydroxypropyl)-piperazine, hexamethyleneimine.

The 2,4-(1H,3H)-quinoazolindione derivatives of the wherein R has the above-given meaning, R is identical with R or, in case R contains an acyloxy radical of the formula S/ E O said R may also represent the radical of the underlying hydroxy compound with an alkoxy benzoic acid of the formula -o OOH or a functional derivative thereof or (b) by cyclizing substituted o-aminobenzamides of the formula II o Nn-oHFon-om-R' with phosgene or with a lower alkyl chloroformiate.

If, according to the process described under para (a), initial products are used wherein the radical of an amine R, which is bound via a nitrogen atom, contains a hydroxyalkyl group, and if 2 mols of alkoxy benzoic acid or of a functional derivative thereof are employed, one obtains the corresponding diesters. The 3-(a-amino-fl-hydroxypropyl)2,4-(1H,3H) quinazolindiones required as starting material for this process may be obtained by various routes of preparation according to the teachings of the corresponding patent application having the same title and the same filing date, i.e., U.S. Ser. No. 49,932, filed June 25, 1970.

The initial products required for the method described under para (b) may be obtained in the usual manner according to analogous processes. As lower alkyl chloroformate it is advisable to use ethyl chloroformate.

The derivatives of the 2,4-(1H,3H)-quinazolindiones according to the present invention are valuable pharmaceuticals. In particular, they are excellent coronary dilators and, in this respect, superior to other known substances of this kind.

With respect to the change in the oxygen tension in the coronary veinous blood, the pharmacological investigation of the vasodilator action on the coronary vessels was carried out in dogs according to the methods described by W. K. A. Schaper and his co-workers (see W. K. A. Schaper, R. Xhonneux, and J. M. Bogaard Uber die kon- 5 tinuierliche Messung des Sauerstoffdruckes im venosen Coronarblut (Naunyn-Schmiedeber-gs Arch. exp. Path. u. Pharrnak. 245, 383389 (1963)). The test preparations were applied intravenously to the narcotized and spontaneously breathing animals. On these test conditions the dilation of the coronary arteries caused by the test substances along with the increase in the coronary blood flow led to an increase in the oxygen tension in the coronary veinous blood. This oxygen tension was measured according to polarographic methods by means of a platin electrode of the Gleichmann-Liibbers type (see U. G1eich mann and D. W. Luebbers Die Messung des Sauerstoffdruckes in Gasen and Fliissigkeiten mit der Platin-Elektrode unter besonderer Beriicksichtigung der Messung im Blut, Pfliigers Arch. 271, 43 1455 (1960)). The heart rate was continuously measured by electronic methods from systolic peaks of the arterial blood pressure. The arterial blood pressure was measured in the known manner in the femoral artery with the aid of an electromanometer of the Statham-strain-gauge type.

The following table gives the results of the pharmocological investigations which were carried through. The preparations Were tested in the form of their respective hydrochlorides:

For a better understanding of the nature and the objects of this invention, reference should be made to the accompanying examples which are of an illustrative rather than a limiting nature. Unless otherwise stated, all temperatures given are in degrees Centigrade.

EXAMPLE 1 if C\ 01130 NCH -EHCH -N(C Hs)a 01330 00 \N/ ('30 l H 38.1 g. (0.1 mol) 3w-diethylamino-fi-hydroxypropyl)-6- 7,8 trimethoxy 2,4 -(1H,3H) quinazolindione are dissolved in 380 cc. chloroform and admixed with 11.1 g. (0.11 mol) triethylamine. Subsequently, while stirring at room temperature, a solution consisting of 25.3 g. (0.11 mol) 3,4,5 trimethoxybenzoyl chloride in cc.

55 chloroform is added dropwise during 30 minutes and Maximal increase Maximal change LD5o dosage in oxygen tension Maximal change in the blood in the coronary in the heart pressure (systolic/ gJkg. MgJkg. veinous blood, in rate in diastolic) in mouse 1.v.

Preparation i.v. Percent Minutes Percent Minutes Percent Minutes 3-['y-diethylamino-fl-(3,4,5-trimethoxybenzoxy) -propyl]-6,7,8-trimethoxy-2,4-(1H,3H)-quinaz01indione 0. 14 0. 2 +92 45 --11 45 i0 3 ['y -morpholino 6 (3,4,5 trimethoxybenz y) pyl] i methOXy-ZA-(1H,3H)-quinazolindione 0. 23 0. 2 +136 20 +16 20 47/42 20 3 ['y piperidino 3 (3,4,5 trimethoxyhenzoxy) propyl] 6,7,8 trimethoxy-2,4-(1H,3H)-q 0. 082 0. 2 45 18 45 13/19 45 3 hexamethyleneimino B (3,4,5 trimethoxybenzoxy) propyl] 6,7,8-trimethoxy-2,4-(1H,3H)-quinaz0lindione 0.063 0. 2 +97 40 -13 40 +18/+7 40 3 ['y pyrrolidino B (3,4,5 trimethoxybenzoxy propyl] 6,7 8 tn 1riethoxy-2,4-(111,311)-quiuazo1indi0ne. 0. 08 0. 2 +67 35 -8 35 -3/20 5 3 [v (4 -methylpiperazino[l] B (3,4,5 trunethoxybenzoxy) ropyl]- 6,7,8-trimethoxy-2,4-(111,311)quinazolindione 0. 17 0. 2 +42 55 9 55 14/17 55 3 ['y diethylamino B (3,4,5 trimethoxybenzoxy) propyl] 6,7 di

methoxy-2,4-(1PT 'iH)-qnina1nlinrlinno 0. 15 0. 2 +26 55 --7 55 -9/B 55 thusly obtained solution is filtered so as to become limpid. 3,4,5-trimethoxybenzoyl chloride in 120 cc. chlorobenzene The aqueous hydrochloric acid solution is then rendered is th n added dropwise while stirring at room temperature. alkaline y the introduction of solid Potassium Carbonate Stirring is continued for 1 hour at room temperature and and the oily, separating reaction Product is dissolved in then for 8 hours at 120 Subsequently, the insolute is ethyl acetato- After drying o Potassium carbonate filtered off and the filtrate is evaporated to dryness in one obtains y the introductlon of anhydrqus gaseous vacuo. The thusly obtained residue is dissolved in dilute hy g Chloride into the ethyl acetate solutlon the 1" hydrochloric acid and the solution is rendered alkaline droChloride 0f the 3 ['Y diothylamino l (3,4,5 by the addition of aqueous potassium carbonate. The Y SQ'P PY J mmethoxy oily, separating reaction product is then dissolved in ethyl qulnazohndlone 111 the form of colorless 10 acetate. After drying over potassium carbonate, and intronoedles melting at 191-192' ducing gaseous hydrogen chloride, the dihydrochloride of Yield: 51 g. (=83.3% of the theoretical) the B 3,4,5 trimethoxybenzoxyethyl piper EXAMPLE 2 azino-[1']) ,8 (3,4,5 trimethoxybenzoxy)-propyl]- (H) OCH3 O N orreoH-oHi-N N-CHzCHrO-CO- Hs O CHsO CH H CH3 C1130 OCH:

43.8 g. (0.1 mol) 3-[7-(4' p hydroXyethyl-piperazino- 6,7,8 trimethoxy 2,4 (1H,3H) quinazolindione is fi hydroxypropyn 6,7,8 trimethOXy 2,4 (1-H precipitated in the form of colorless needles melting at 154156 Yield: 54 g. of the theoretical 3H) quinazohndlone are suspended with the addition of 30 Analogously to the descriptions given in Exaliples 1 11101) triothylammo 111 400 anhydrous and 2 the following compounds of the present invention chlorobenzene. A solution consisting of 46 g. (0.2 mol) may be prepared:

General formula:

Melting point yd ochloride), (B1) (R2)m R v degrees 6,7,8-(OCH 34,5- OCH 150-152 a)a a): u

6,7,8-(0CH3)3.::':.: 3,4,5-(OCH /N 155 L 6,7,8(0OHa)a-::-:; 3,4,5- 001193 158 6,7,8- OCH 3,4,5- OCH 175 3):; a)a O S 6,7,8-(OCHa)s-.' 3,4,5-(0 CHM N/ \s z 6,7,8-(OCH3)a.:::.:. 3,4,5-(OCH (IF/Ha 122-125 -N'CH1CHOHg-OCH3 6,7,8-(OCHs)a.:.;.-.:'. 3,4,5-(0 CHM (3H3 2 NCH5CnH5 6,7,8-(0 01103.32; 3,4,5-(OCH3)3 CHa 9 TABLEContinued Melting point hi i f' (R1). (Re... R i re 6,7,8-(OGH3); 3,4,5-(OOH (EH 116-118 6,7,8-( CH3): 3,4,5-(OCH3); (3H3 1 3 9O --NCHaCHzCHzN H 6,7,8-(OCH3) 3,4,5-(OOH3); -N(C4Ho): 3 182-184 6,7-(0 CH3): 3,4,5-(OCH3)3 -N(CaH5)2 a 3 90 1 Dihydrochloride. 1 Decomposition. 3 Hydrochloride.

EXAMPLE 3 pressure of 70 atmospheres. The reaction product is 2-nitro-3,4,5-trimethoxy-N- y-diethylamino-B- hydroxypropyl)-benzamide 82.6 g. (0.3 mol) 2-nitro 3,4,5 trimethoxybenzoyl chloride are dissolved in 200 cc. anhydrous benzene and added dropwise, while stirring, to a solution consisting of 43.8 g. (0.3 mol) y-diethylamino fl hydroxypropylamine and 30.3 g. (0.3 mol) triethylamine in 500 cc. anhydrous benzene. Stirring is continued for 3 hours under reflux and after cooling down, the filtrate is evaporated to dryness in vacuo. For further purification purposes the crude product is dissolved in dilute hydrochloric acid and, after filtration, the filtrate is rendered alkaline by the addition of an aqueous potassium carbonate solution. The base which hereby separates in the form of an oil, is dissolved in ethyl acetate and washed several times with water. After drying over potassium carbonate the ethyl acetate solution is concentrated in vacuo and thus obtained is the 2-nitro-3,4,5- trirnethoxy N ('y diethylamino- 3-liydroxypropyl)- benzamide in the form of a yellowish oil.

Yield: 91 g. (=79% of the theoretical) 2-nitro-3 ,4,5-trimethoxy-N ['y-diethylamino-B- (3 ,4,5- trimethoxybenzoxy) -propyl1-benzamide 38.5 g. (0.1 mol) 2-nitro-3,4,5-trimethoxy-N-('y-diethylamino-fi-hydroxypropyl)-benzamide and 15.15 g. (0.15 mol) triethylamine are dissolved in 200 cc. anhydrous benzene and admixed with stirring with a solution consisting of 34.5 g. (0.15 mol) 3,4,5-trimethoxybenzoy1 chloride in 150 cc. anhydrous benzene. Subsequently, the reaction mixture is heated to the boil and stirring is continued for 6 hours under reflux. After cooling down the reaction product is stirred out with 300 cc. water and the benzene layer is separated. Subsequently, the benzene layer is shaken out with dilute hydrochloric acid. The aqueous hydrochloric acid solution is rendered alkaline by the addition of aqueous potassium carbonate solution and the base which separates in the form of an oil is dissolved in ethyl acetate. The thusly obtained ethyl acetate solution is washed with water and evaporated to dryness, after drying over potassium carbonate, in vacuo. For further purification the crude product is recrystallized from alcohol. Thus obtained is the 2-nitro-3,4,5- trimethoxy-N- ['y-diethylamino-B-(3,4,5 trimethoxybenzoxy)-propyl]-benzamide in the form of light yellow crystals melting at 107.

Yield: 46 g. (=79.5% of the theoretical) 2-amino-3 ,4,5-trimethoxy-N- ['y-diethylamino-p- (3,4,S-trimethoxybenzoxy)-propyl]-benzamide 58 g. (0.1 mol) 2-nitro-3,4,5-trimethoxy-N-[-y-diethylamino-1843,45 trimethoxybenzoxy)-propyl]-benzamide are dissolved in 250 cc. methanol and hydrogenated at 30-40" in the presence of Raney nickel at a hydrogen sucked oif from the catalyst and the filtrate is evaporated to dryness in vacuo. The oily residue is dissolved in ethyl acetate and by the addition of etheric hydrochloric acid the dihydrochloride of the 2-arnino-3,4,S-trimethoxy-N- -diethylamino {3 (3,4,5-trimethoxybenzoxy)propyl]- benzamide is precipitated in the form of colorless needles having a decomposition point of 75.

Yield: 49 g. (=78.7% of the theoretical) 3 ['y-diethylamino-fl- (3 ,4,5 -trimethoxybenzoxy) -propyl] 6,7,8-trimethoxy-2,4-( 1H,3H) -quinazolindione acid solution is rendered alkaline by the addition of aqueous potassium carbonate solution. The oily, separating reaction product is dissolved in ethyl acetate and after drying over potassium carbonate one obtains by the introduction of anhydrous hydrogen chloride into the ethyl acetate solution the hydrochloride of the 3-[ y-diethylamino fl (3,4,5-trimethoxybenzoxy)-propyl]-6,7,8-trimethoxy-2,4-(1H,3H) -quinazolindione in the form of colorless needles melting at 191-192.".

Yield: 38 g. (=62% of the theoretical) The same product is also obtained by reacting in the usual manner Z-amino 3,4,5 trimethoxy-N-(y-diethylamino B 3,4,5 trimethoxybenzoxy-propyl)-benzamide with phosgene.

What is claimed is:

'1. A basically substituted 2,4-(lH,3H)-quinazolindione derivative having the formula RD (1) O wherein R stands for a radical selected from the group consisting of di-C -C alkylamino, N methyl-benzylamino, N-methyl N cyclohexylamino, N-methyl-allylamino, N-mcthyl-piperazino, N-methyl-N-(piperidinopropyl -amino, N-methyl-N- (methoxy-n-propyl -amino, hexamethylene-imino, morpholino, thiomorpholino, pyrrolidino and piperidine; R stands for methoxy; R stands for alkoxy groups having 1-4 carbon atoms; In stands for an integer selected from the group consisting of 1,2 and 3; and It stands for an integer selected from the group consisting of 2 and 3, and the hydrochloric acid addition salts thereof.

2. 3-[ y-diethylamino ,B (3,4,5-trimethoxybenzoxy)- propy1]-6,7,8-trimethoxy 2,4 (lH,3H)-quinazolindione, and the hydrochloric acid addition salts thereof.

3. 3-[' -morpholine-fi-(3,4,5 trirnethoxybenzoxy)-propropyl]-6,7,8-trimethoxy 2,4 (lH,3H)-quinazolindione, and the hydrochloric acid addition salts thereof.

4. 3-['y-Piperidino 13 (3,4,5-trimethoxybenzoxy)-propyl]-6,7,8-trimethoXy-2,4-(1H,3H)-quinazolindione, and the hydrochloric acid addition salts thereof.

5. 3-[' -hexamethyleneimino B (3,4,5-trimethoxy)- propyl]-6,7,8-trimethoxy 2,4 (1H,3H)-quinazolindione, and the hydrochloric acid addition salts thereof.

6. 3-['y-pyrrolidino-fl-(3,4,5 trimethoxybenzoXy)-propyl] -6,7,8-trimethoxy-2,4-( lH,3H)-quinazolindione, and the hydrochloric acid addition salts thereof.

References Cited UNITED STATES PATENTS 3,274,194 9/1966 Hayao 2-60256.4

ALEX MAZEL, Primary Examiner R. V. RUSH, Assistant Examiner US. Cl. X.R. 

